ABSTRACT Increasing evidence suggest that the interactions between diet and the gut microbiota may play a critical role in promoting or alleviating intestinal inflammation. However, little is known about the mechanisms involved. Free fatty acids provide important energy sources as dietary nutrients, and act as signaling molecules in various cellular processes. Most notable among the free fatty acids? targets are mammalian G protein-coupled receptors. GPR120 (also known as free fatty acid receptor 4, FFAR4) has been identified as a receptor for long-chain fatty acids (LCFA) from dietary products, and has a critical role in various physiological homeostasis mechanisms, such as adipogenesis, and regulation of appetite. Its agonists are suggested as therapeutic targets for diabetes, metabolic disorders and inflammatory diseases. Various ?-3 or ?-6 polyunsaturated FAs activate GPR120 in the micromolar concentration range. GPR120 agonism by various ligands, more particularly by the omega 3 (?- 3, n-3; ?-linolenic acid, ALA) polyunsaturated fatty acids (PUFA), has been shown to result in varied potentially beneficial biological effects. However, the mechanisms involved are still largely unknown. It is also unknown if and how GPR120 regulates intestinal homeostasis. We have established recently that GPR120-/- mice developed more severe colitis upon inflammatory insult, and administration of GPR120 agonist inhibited colitis development. We showed that both T cells and dendritic cells (DC) expressed GPR120 in addition to IEC and other cells. Transfer of GPR120-/- CD4+ T cells from CBir1 TCR transgenic (CBir1 Tg) mice, which are specific for an immunodominant microbiota antigen CBir1 flagellin, induced more severe colitis in Rag-/- mice with decreased IL-10 producing T cells in the intestinal lamina propria compared to wild-type (WT) T cells. In this application, we hypothesize that GPR120 contributes to intestinal homeostasis through regulation of T cell and DC function, which leads to preservation of intestinal immune homeostasis and inhibition of inflammatory bowel diseases. Furthermore, GPR120 agonists will prevent and treat colitis. We will define the mechanisms by which GPR120 regulates T cell function (Aim 1), and intestinal DC function (Aim 2). Finally we will determine the effects of GPR120 agonists in preventing and treating colitis (Aim 3). This highly translational project will provide novel insights into dietary intervention of IBD and point to GPR120 as a potential therapeutic target for treatment of IBD patients.